We propose to pursue observations by the Principal Investigator and each of the two Co-Investigators that relate genetic and expression differences in IFNgamma to gender bias in MS. MS is two to three times as common in women, yet pursues a more benign course in women. Two of the investigators have found that the 12 CA-repeat allele of an intron 1 polymorphism in the IFNgamma gene (IFNG), which is associated with increased expression of IFNgamma, is underrepresented in men relative to women with MS and to controls in ethnically different populations. Other polymorphisms in linkage disequilibrium (LD) reveal similar findings, and a LD study suggests that this gender bias trait maps to the 100 kb surrounding the gene. Another of the Co-Investigators has independently found a gender bias in IFNgamma expression such that peripheral blood mononuclear cells (PBMCs) of patients with MS, particularly women, over-express IFNgamma in response to disease-related and unrelated antigenic stimuli. Our hypothesis is that genetic variants in IFNG explain some or all of this variation. The Specific Aims of this application are: 1) to extend the genetic observations to all of our populations and to fine map this trait further to the locus; 2) to analyze the functional significance of these genetic variants using appropriate allelic reporter constructs; and 3) to correlate genotype of individuals with phenotype (TH1/TH2) of cells of patients with MS and with the level of IFNgamma expression. The long-term goals of this project are to understand gender bias in susceptibility to MS and to pursue a genetic association in a complex genetic disease (MS) to yield definitive conclusions regarding causality. If successful, this paradigm could be applied to a number of similar genetic association studies.